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To investigate whether fetal sex affects the impact of classical GDM risk factors on the diagnosis of gestational diabetes (GDM) as well as on related adverse pregnancy outcomes.This retrospective observational study concerned 206,917 singleton live births born to 170,126 women aged 15-45 over the years 2010-2018 in Tuscany, Italy. GDM was identified by administrative data-sources in 21,613 pregnancies (10.5%) by assessing, through multiple logistic models, whether fetal sex modified the risk of GDM driven by maternal risk factors, and whether it modified the risk of adverse outcomes such as prematurity (birth ≤ 37th gestational week), large for gestational age (LGA), unplanned caesarean sections, or 5-min-Apgar-index ≤ 7 in pregnancies with GDM.GDM was diagnosed in 21,613 pregnancies (10.5%). Male fetal sex predicted a higher adjusted risk of GDM: OR = 1.05(95% CI: 1.01-1.07); p 0.0009. In pregnancies with female sex, pre-pregnancy obesity amplified the risk of GDM: OR = 1.09(95% CI: 1.01-1.19); p = 0.04. In pregnancies with GDM, carrying a female fetus increased the risk of LGA associated with pregestational obesity OR = 1.45(95% CI: 1.15-1.81); p = 0.001, and in primiparous pregnancies, it protected mothers from the risk of unplanned caesarean sections OR = 0.80(95%CI: 0.67-0.92); p = 0.001.While male fetal sex is associated with rise in the risk of GDM, giving birth to a girl amplifies the excess GDM risk driven by pregestational obesity, thus increasing the risk of LGA in pregnancies with GDM. Additionally, female fetal sex in pregnancies with GDM seems to protect from the risk of unplanned caesarean sections in primiparous pregnancies.

The diabetic foot (DF) is one of the most feared conditions among chronic complications of diabetes, which affects a growing number of patients. Although exercise therapy (ET) has always been considered a pillar in the treatment of patients at risk of DF it is not usually used. Several causes can contribute to hindering both the organization of ET protocols for Diabetes Units and the participation in ET programs for patients at different levels of risk of foot ulceration. The risk of favoring the occurrence of ulcers and the absence of clear evidence on the role played by ET in the prevention of ulcers could be considered among the most important causes leading to the low application of ET. The increased availability of new technologies and in particular of systems and devices equipped with sensors can enable the remote monitoring and management of physical activity performed by patients. Consequently, they can become an opportunity for introducing the systematic use of ET for the treatment of patients at risk. Considering the complexity of the clinical conditions that patients at risk or with diabetic foot ulcer can show, the evaluation of how patients perform the ET proposed can consequently be very important. All this can contribute to improving the treatment of patients and avoiding possible adverse effects. The aim of this brief review was to describe that the use of new technologies and the assessment of the execution of the ET proposed allows an important step forward in the management of patients at risk.

Background Limited Joint Mobility (LJM) is a dreaded complication of Diabetes Mellitus (DM). During the last half century, LJM has been studied in patients of different age because it has been considered useful for the monitoring of a patient's condition and for the prevention of vascular disease and diabetic foot. Objectives The main aims of this review are to describe the relationship between DM and joint mobility as well as its prevalence and assessment. We have also investigated the role of LJM in the development of diabetic foot ulcers. Methodology An in-depth literature search was conducted to identify studies that examined the prevalence and characteristics of LJM in patients with DM of different types, age, durations and chronic complications. Results Many factors (therapy improvements, population characteristics and different evaluation methods) concur to hinder an exact assessment of the prevalence of LJM. However, it has been confirmed that LJM is widespread among patients with DM and may affect more than two-thirds of them in addition to being a major risk factor for foot ulcer. Its role in the monitoring of a patient's condition is also important for the definition of risk thresholds such as in patients with diabetic foot. The efficacy of exercise therapy for the treatment of LJM, also in patients at risk of foot ulcer, has not been discussed. Conclusion Difficulties encountered in the definition of the prevalence of LJM may hinder its study and the establishment of preventive interventions. However, LJM plays a key role in the monitoring of patients, especially those at risk for ulcer.

To provide data on hospitalization and incidence rates of Charcot neuroarthropathy (CN) and its relation to lower limbs' amputations/revascularizations in population with diabetes of Italy as well as of one of its regions (Tuscany).Hospitalizations with CN diagnosis (codes ICD-9-CM: 7130, 7135, 7138) have been recorded in people with diabetes over years 2003-2013 in Italy and 2008-2015 in Tuscany. Amputations, peripheral vascular disease, revascularizations and infections were likewise evaluated.Between 2003 and 2013 CN hospitalizations were very infrequent in Italy ranging between 14×100,000 and 11×100,000 patients with diabetes. In Tuscany they declined to a minimum of 7×100,000 patients in 2015, after a previous increase to a maximum of 22×100,000 (p=NS for both). Yearly CN incidence remained constant in Italy, declining in Tuscany to a minimum of 3.4×100,000 diabetic patients in 2015 (p=0.047). CN patients were younger and with longer length of hospital stay than those with non-Charcot diabetic foot (p0.05 for both). Amputation and infection rates were manifold higher in CN patients than in those with non-Charcot diabetic foot, while the revascularization rate was similar in both.Over last decade, in Italy and Tuscany yearly CN incidence and hospitalization rates concerned only a small percentage of patients, remaining constant over years and declining in Tuscany in the last couple of years. CN was significantly associated to younger age, longer hospital stay and greater risk of amputations and infections while the need of revascularization was similar to that of non-Charcot diabetic foot.

Background The burden of type 1 diabetes (T1D) is growing worldwide, stressing the requirement to limit the threat of its long-term complications. In this regard, the development of methods for the early diagnosis and non-invasive monitoring of vascular abnormalities is widely recognized as one of the greatest priorities of the clinical research in this field. Objective To assess the deterioration of physiological properties extracted from laser Doppler flowmetry (LDF) signals of microvascular perfusion and, secondly, to investigate their association with the quality of long-term metabolic control. Methods Microvascular perfusion was recorded at the hallux of 63 control subjects and 47 T1D patients, whose glycaemic control was characterized in terms of the annual average levels of glycosylated haemoglobin (HbA1c). Pulse Decomposition Analysis was applied to the LDF data, in order to derive non-invasive markers of vascular stiffness based on a multi-Gaussian representation of the peripheral pulse waveforms; furthermore, wavelet transform analysis was used to evaluate the microvascular myogenic vasomotion and, finally, a physiological model of the reactive hyperaemia to a local thermal stimulus at 43 was used to test the integrity of the neurovascular pathways. Results Compared to the control group, T1D patients showed a lower microvascular perfusion at baseline, and a larger vasodilatory reserve upon local heating, but no significant difference in myogenic activity. Moreover, the results of the PDA carried out on the LDF pulse waves, indicate the presence of a significant strong relation between large artery stiffness and the overall loss of glycaemic control over the past year.

The microvascular perfusion is modulated by physiological functions, which have been associated with specific frequency ranges. Although cardio-respiratory interactions have been widely analyzed at a macrocirculation level, only few studies have been conducted with the aim to understand the effect of breathing on the peripheral circulation. Diabetic microangiopathy is characterized by structural and functional alterations of the blood microvessels, which reflect in a modification of the physical properties of peripheral microvascular beds, such as vascular stiffness. A wavelet phase coherence (WPC) analysis was performed to elucidate the time-phase relationship between the respiratory activity and vascular-dependent features of the peripheral pulse, reconstructed by means of a novel multi-Gaussian modeling algorithm. The present WPC analysis was conducted on a group of 24 healthy volunteers, mean age 30±15 years, in comparison with 21 type-1 diabetic (T1D) subjects, mean age 26±3 years, in order to detect the effects of T1D on the physiological coupling between breathing and microcirculation. The peripheral cutaneous perfusion was assessed on the pulp of the index finger with the laser Doppler flowmetry (LDF) technique, while the respiratory signal was simultaneously recorded with a wearable chest band. In 17 out of the 24 control subjects involved (i.e., 71%), significant WPC values were identified in the respiratory frequency range (0.145-0.6 Hz), with respect to the area beneath the diastolic portion of the peripheral pulse (median WPC: 77.9%). This outcome indicates that the diastolic phase of the pulse exhibits a marked periodicity linked to the breathing activity. The analysis conducted on the T1D group highlighted a loss of synchronization, with significant WPC levels found in only 33% of the investigated subjects. These results suggest that the proposed method is able to detect the detrimental effects of T1D on the blood microcirculation. Disclosure A. Perrella: None. M. Sorelli: None. P. Francia: None. L. Capirchio: None. R. Anichini: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company, AstraZeneca. Speaker's Bureau; Self; Merck & Co., Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Sanofi, Janssen Pharmaceuticals, Inc.. Research Support; Self; Grünenthal Group. A. de Bellis: Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca, Novo Nordisk A/S. Research Support; Self; Grünenthal Group. M. Gulisano: None. L. Bocchi: None.

In patients with diabetic foot (DF) the risk of developing cardiovascular events or renal failure is strongly increased. While DF is more frequent in males, it is yet unknown if there is a gender difference about cardiovascular events or renal failure incidence in patients with diabetic foot. The aim of this study was to evaluate the risk of hospitalization for cardiovascular events (ASCVD: heart attack, ischemic stroke or heart failure) or chronic renal failure (CKD), stratified by gender, in a population of diabetic patients living in Tuscany from 2012 to 2016. On the basis of administrative data bases, patients living in Tuscany at the 1st of January 2012 were divided into 2 subgroups: patients previously hospitalized for diabetic foot (ulcers, infections, major or minor amputations, gangrene or Charcot foot) and patients without history of hospitalization for diabetic foot. Data were collected from the regional hospitalization registry, and in the two groups the risk of developing ASCVD or CKD by the Cox regression corrected by age and comorbidities (Charlson Index of previous hospitalizations) separately in males and females was evaluated. 240238 patients with diabetes (121442 males, 118796 females) were identified. After the corrections made by age, sex and Charlson index, males showed a major risk of developing diabetic foot (DF): Odds Ratio (OR):2.018 (95% CI:1.901-2.141); p Disclosure R. Anichini: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company, AstraZeneca. Speaker's Bureau; Self; Merck & Co., Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Sanofi, Janssen Pharmaceuticals, Inc.. Research Support; Self; Grünenthal Group. L. Policardo: None. P. Francesconi: None. P. Francia: None. A. de Bellis: Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca, Novo Nordisk A/S. Research Support; Self; Grünenthal Group. M. Gulisano: None. G. Seghieri: None.

Among diabetic patients, microangiopathy represents a relevant cause of morbidity and mortality. Diabetes induces detrimental changes in the biomechanical characteristics of blood microvessels, and fuels the development of a dysfunctional vascularization. Since the structural properties of the circulatory system affect the microvascular pulse, the aim of this study was to detect these vascular alterations through a model-based quantitative analysis of its waveform. Baseline microvascular perfusion was recorded on the hallux with a laser Doppler flowmeter. 54 healthy subjects (age: 34 ± 26 years) and 22 type 1 diabetic (T1D) patients without known cardiovascular complications and smoking history (age: 34 ± 17 years) were compared. A novel multi-Gaussian decomposition algorithm was applied to reconstruct the heartbeat-related oscillations, which were evaluated according to normalized and physiologically-motivated shape descriptors. Eight out of the nine properties assessed significantly differed between the groups (p < 0.001), indicating that the proposed pulse modeling method is sensitive to the effects of T1D on the peripheral perfusion.

This study has been performed in diabetic type 2 patients with pain due to peripheral artery disease (PAD) in order to evaluate the efficacy and tolerability of tapentadol prolonged release (PR). Methods. 25 patients with type 2 diabetes (13 F and 12 M) were admitted in the study. The evaluation of the analgesic efficacy of tapentadol PR was based on both the assessment of the intensity of the pain (NRS scale from 0 to 10) and the nature of the pain (DN4 questionnaire) and on assessment of the patient’s quality of life and state of health (SF-12 Health Survey). Study duration was 3 months: a baseline visit and follow-up included visits after 1 week, 1 month, 2 months, and 3 months. Results. At the beginning of the study, the mean intensity of the pain was 7.88 ± 1.17 on the NRS scale and at visit 2 it reduced in a statistically significant way; at the end of the treatment with tapentadol PR, the mean intensity was 2.84 points on the NRS scale. Conclusion. In type 2 diabetic patients with chronic severe pain due to PAD, tapentadol PR reduced pain intensity, improving the quality of life.

Evaluation of how ankle joint mobility (AJM) can be useful in the identification of patients with diabetes at risk of foot ulcer (FU).Plantar and dorsal flexion of foot were evaluated using an inclinometer in 87 patients (54 type 2 and 33 type 1), and 35 healthy sex- and age-matched control subjects. Patients with diabetes were followed up for diagnosis of FU over the next 8 years and subsequently, patients were subdivided into: those without a history of FU (18 type 1 and 33 type 2), those who had a history of FU detected before baseline evaluation (14 type 2) and those who had history of first ulceration detected by the 8th year of the evaluation period (7 type 2).Aging and diabetes caused a significant reduction in mobility of each of the movements investigated (p0.001), whereas after adjusting for the confounding effect of age, diabetes specifically reduced plantar flexion (p0.0001). AJM was significantly lower in those with history of previous FU compared to all the other groups (p0.001). The first ulceration was detected in the same foot presenting lower AJM in 17 of the 22 subjects with diabetes with history of ulcer (77.27%).Diabetes and aging reduce AJM although diabetes seems to reduce plantar flexion to a more specific extent. Reduced AJM is mostly associated with a previous history of FU. The evaluation of AJM is a valid and reliable ulcer risk scale that indicates which foot is at higher ulcer risk.

Exercise has been proved to be safe during pregnancy and to offer benefits for both mother and fetus; moreover, physical activity may represent a useful tool for gestational diabetes prevention and treatment. Therefore, all women in uncomplicated pregnancy should be encouraged to engage in physical activity as part of a healthy lifestyle. However, exercise in pregnancy needs a careful medical evaluation to exclude medical or obstetric contraindications to exercise, and an appropriate prescription considering frequency, intensity, type and duration of exercise, to carefully balance between potential benefits and potential harmful effects. Moreover, some precautions related to anatomical and functional adaptations observed during pregnancy should be taken into consideration. This review summarized the suggested recommendations for physical activity among pregnant women with focus on gestational diabetes.

Background. Taurine transporter gene expression (RNA-TauT) has a role in retinal cell function and is modulatedin vitroandin vivoby hyperglycemia and/or oxidative stress. This study was aimed at testing whether RNA-TauT gene expression is modified in blood mononuclear peripheral cells (MPCs) of type 1 diabetic patients, is related to plasma markers of oxidative stress or endothelial dysfunction, or, finally, is related to presence of retinopathy.Methods. RNA-TauT was measured in MPCs by real-time PCR-analysis in 35 type 1 diabetic patients and in 33 age- and sex-matched controls, additionally measuring plasma and cell taurine and markers of oxidative stress and endothelial dysfunction.Results. RNA-TauT, expressed as2-ΔΔCt, was significantly higher in MPCs of type 1 diabetic patients than in controls [median (interquartile range): 1.32(0.31) versus 1.00(0.15);P=0.01]. In diabetic patients RNA-TauT was related to HbA1c (r=0.42;P=0.01) and inversely to plasma homocysteine (r=-0.39;P=0.02) being additionally significantly higher in MPCs of patients without retinopathy [(n=22); 1.36(0.34)] compared to those with retinopathy [(n=13); 1.16(0.20)], independently from HbA1c or diabetes duration.Conclusions. RNA-TauT gene expression is significantly upregulated in MPCs of type 1 diabetes patients and is related to HbA1c levels and inversely to plasma homocysteine. Finally, in diabetes patients, RNA-TauT upregulation seems to be blunted in patients with retinopathy independently of their metabolic control or longer diabetes duration.

Obesity and weight increase during adult life are strong predictors of type 2 diabetes. Whether fasting plasma glucose (FPG) is likewise related to body weight as well as with its increase during the adult life in obese-overweight people and whether this relationship is different between the genders is the question asked by the present study. We measured FPG in 1063 overweight-obese subjects (395M/668F) with BMIor =25 kgm(-2) and classified with no history of diabetes and with a FPG7 mmol/l, who consequently came to the Outpatient Clinic of our Diabetes Unit to obtain dietetic advice. Weight increase was determined as the difference between actual weight and weight at 18 years (weight-diff), including only patients with weight-diff0. By univariate analysis age, BMI, waist circumference and weight change were loosely related to FPG in both sexes, even if the relation between plasma glucose and anthropometric variables was more consistent in females. By multivariate regression analysis, after adjusting for age, waist circumference, menopausal status and smoking habit, FPG was significantly related to both waist circumference and weight-diff only in women. Odds Ratio for fasting hyperglycaemia (FPG6.11 mmol/l), for each S.D. unit increase in weight-diff, after adjusting for age, waist circumference, smoking habit and menopausal status was 1.272; 95% CI: 0.863-1.901 (p=ns) for males and 1.800; 95% CI: 1.239-2.652 (p=0.002) for women. In conclusion our findings suggest that in non-diabetic overweight-obese people, after controlling for main cofounders, anthropometric variables and in particular waist circumference and weight change after 18 years are linearly related to FPG in women, independently predicting the risk of fasting hyperglycaemia only in these latter.

OBJECTIVE— The aim of this article was to define the metabolic phenotype of pregnant women with one abnormal value (OAV) during an oral glucose tolerance test (OGTT) and to test whether OAV could be considered metabolically comparable to gestational diabetes mellitus (GDM) or a specific entity between GDM and normal pregnancy. RESEARCH DESIGN AND METHODS— After 100-g 3-h OGTTs, 4,053 pregnant women were classified as having GDM, OAV, or normal glucose tolerance (NGT). Those with OAV were subdivided into three subgroups: fasting hyperglycemia (one abnormal value at fasting during an OGTT), 1-h hyperglycemia (one abnormal value at 1 h during an OGTT [1h-OAV]), or 2- or 3-h hyperglycemia (one abnormal value at 2 or 3 h during an OGTT). As derived from the OGTT, we measured insulin sensitivity (insulin sensitivity index [ISI] Matsuda) and insulin secretion (homeostasis model assessment for the estimation of β-cell secretion [HOMA-B], first- and second-phase insulin secretion). The product of the first-phase index and the ISI was calculated to obtain the insulin secretion–sensitivity index (ISSI). RESULTS— GDM was diagnosed in 17.9% and OAV in 18.7% of pregnant women; women with GDM and OAV were older and had higher BMI and serum triglyceride levels than those with NGT (all P < 0.05). Women with NGT had the highest ISI followed by those with OAV (−21.7%) and GDM (−32.1%). HOMA-B results were comparable with those for OAV and GDM but significantly (P < 0.01) lower than those for NGT; first- and second-phase insulin secretion appeared progressively reduced from that in women with NGT to that in women with OAV and GDM (P < 0.01). ISSI was higher in women with NGT than in women with either OAV (−34%) or GDM (−51.7%) (P < 0.001). Among OAV subgroups, the 1h-OAV subgroup showed the lowest ISSI (P < 0.05). CONCLUSIONS— OAV and GDM are clinically indistinguishable, and both groups are different from women with NGT. Women with GDM and OAV showed impaired insulin secretion and insulin sensitivity, although these defects are more pronounced in women with GDM. Compared with other OAV subgroups, 1h-OAV could be considered a more severe condition.

Background Incidence of ischemic stroke and associated in-hospital mortality is decreasing in Western populations, while the prevalence of diabetes, a well-known risk factor for ischemic stroke, is progressively rising. This study was aimed at evaluating the effect of diabetes on ischemic stroke hospitalization and in-hospital mortality after ischemic stroke. Methods Discharges with diagnosis of ischemic stroke were identified in a database containing all hospitalizations of resident population of Tuscany, Italy, over years 2004–2011. Cases with diabetes were identified through specific drug prescriptions, official certifications or previous hospital diagnosis. Rates of annual ischemic stroke incidence and related in-hospital mortality were separately calculated for gender and age class, in subjects with and without diabetes. Results Sixty-five thousand one hundred sixty-five hospital discharges with ischemic stroke diagnosis were identified. Diabetes was associated with increased risk of stroke odds ratio(95% confidence interval):1.31(1.28–1.34) in men and 1.24(1.21–1.37) in women. Diabetic women, compared with men, had a higher in-hospital mortality risk after ischemic stroke (odds ratio:1.32; 1.06–1.64), whereas in non-diabetic subjects, there was no difference between genders. Incidence of ischemic stroke has declined in non-diabetic subjects, except for women aged ≤70 years; a similar reduction was observed for in-hospital mortality. Among diabetic patients, conversely, annual incidence of ischemic stroke rose by 3% in the elderly people (>70 years), and annual mortality trend remained unchanged. Conclusions In the last decade, the incidence of ischemic stroke and of related in-hospital mortality declined in persons without diabetes, while increasing among diabetic patients of advanced age. Women with diabetes, compared with men, had a higher in-hospital mortality risk. Copyright © 2014 John Wiley & Sons, Ltd.

Abstract —Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the ScaI and BstXI polymorphisms of the human ANP ( hANP) gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively ( P ScaI mutated allele ( A 1 ) was significantly lower in hypertensive than in control subjects (11% versus 19%, P =0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%; P A 1 allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59; P =0.003) but not with hypertension. In the same model, the frequency of the BstXI mutated allele ( T 708 ) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59; P ScaI polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of BstXI polymorphism are positively associated with microalbuminuria. hANP gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.

It is well recognized that the actions of androgens alone do not explain the hyperplastic development of the gland that occurs in elderly men. The increasing number of reports confirming the lack of mitogenic activity of androgens coupled with the powerful mitogenic activity of growth factors and the discovery of growth factor receptors led to an increased interest in the putative role of growth factors in prostate physiopathology. We have previously demonstrated the presence and the cellular localization of epidermal growth factor and of the related peptide, transforming growth factor-α, together with their common receptor in the epithelial compartment of the human hyperplastic prostate tissue (BPH). In the present study we examined the expression and cellular localization of messenger ribonucleic acid (RNA) encoding keratinocyte growth factor (KGF) and its receptor in human hyperplastic prostate tissue. RT-PCR of total RNA extracted from BPH tissues documented the presence of transcripts for KGF and its...

OBJECTIVE: To analyze hospitalization for lower extremity amputations (LEAs) and amputee rates in persons with and without diabetes in Italy. RESEARCH DESIGN AND METHODS: All patients with LEAs in the period 2001-2010 were identified analyzing the National Hospital Discharge Record database. For each year, amputee and hospitalization rates for LEAs were calculated either for persons with diabetes or without. Time trend for major and minor amputations were analysed. RESULTS: From 2001 to 2010 a mean annual number of 11,639 individuals underwent a lower extremity amputation: 58.6% had diabetes accounting for 60.7% of total hospitalizations. In 2010, the crude amputee rate for LEAs was 20.4 per 100,000 inhabitants: 247.2 for 100.000 persons with diabetes, and 8.6 for those without diabetes. Having diabetes was associated to an increased risk of amputation (Poisson estimated RR 10.9, 95%CI 9.4-12.8). Over the whole period, a progressive reduction of amputee rates was observed for major amputations either among persons with diabetes (-30.7%) or without diabetes (-12.5%), while the rates of minor amputations increased progressively (+22.4%) among people without diabetes and were nearly stable in people with diabetes (-4.6%). A greater number of minor amputations were performed among persons with than without diabetes: in 2010, the minor-to-major ratio among persons with diabetes (2.5) was more than twice than in those without diabetes (1.0). CONCLUSIONS: The nationwide analyses confirm a progressive reduction of hospitalization and amputee rates for major LEAs, suggesting an earlier and more diffuse approach aimed at limb salvage.

Taurine acts as antioxidant, cell osmolyte, modulator of glucose metabolism, and plays a role in the retinal function. It is 103-fold more concentrated in the intracellular than in the extracellular milieu due to a specific taurine-Na-dependent transporter (TauT), which is upregulated by hypertonicity, low extracellular taurine, or oxidative stress and acutely downregulated ‘in vitro’ by high glucose concentrations. Aim of this study was to investigate whether TauT expression was modified in mononuclear peripheral blood cells (MPC) of type 2 diabetic patients with or without micro/macrovascular complications. Plasma taurine, as well as other sulphur-containing aminoacids (assayed by HPLC) and TauT gene expression (assayed by real-time PCR analysis) were measured in MPC of 45 controls and of 81 age-and-sex matched type 2 diabetic patients with or without micro/macrovascular complications. Median value (interquartile range) of plasma taurine was significantly lower in diabetic patients than in controls [28.7 (13.7) μmol/l vs. 46.5 (20.3) μmol/l; P

Insulin-like growth factor I (IGF-I) receptors were characterized in membranes obtained from prostate tissue of patients affected by benign prostatic hyperplasia (BPH) before and after treatment with a GnRH agonist analog. Binding of [125I]IGF-I to membranes obtained from untreated patients was specific and time and temperature dependent. Analysis of the binding data yielded two classes of binding sites, one of high affinity (Kd, 10(-11) mol/L) and one of lower affinity (Kd, 10(-9) mol/L). BPH membrane preparations were affinity-cross linked to labeled IGF-I, and then subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Analysis by autoradiography revealed one labeled protein with an apparent Mr = 300K under nonreducing conditions and two labeled protein with Mr = 270K and Mr = 130K under reducing conditions. Excess unlabeled IGF-II reduce both of them, whereas the same excess of IGF-I completely abolished them. In membrane preparations of prostatic tissues from patients affected by BPH and treated for 2 months with a GnRH agonist analog, the binding capacities of both binding sites were significantly higher than those of BPH tissue from untreated patients, whereas binding affinities were unchanged. The IGF-I receptor in BPH prostate tissue of untreated patients was mainly localized in the basal layer of the epithelium, as demonstrated by immunohistochemical staining, whereas in the tissue from treated patients positive staining was found also in the glandular epithelium. These results demonstrate that: 1) specific binding sites for IGF-I are present in prostatic tissue from patients with BPH, 2) androgen deprivation increases their binding capacities and seems to modify their epithelial localization.

The aim of this article was to define the metabolic phenotype of pregnant women with one abnormal value (OAV) during an oral glucose tolerance test (OGTT) and to test whether OAV could be considered metabolically comparable to gestational diabetes mellitus (GDM) or a specific entity between GDM and normal pregnancy.After 100-g 3-h OGTTs, 4,053 pregnant women were classified as having GDM, OAV, or normal glucose tolerance (NGT). Those with OAV were subdivided into three subgroups: fasting hyperglycemia (one abnormal value at fasting during an OGTT), 1-h hyperglycemia (one abnormal value at 1 h during an OGTT [1h-OAV]), or 2- or 3-h hyperglycemia (one abnormal value at 2 or 3 h during an OGTT). As derived from the OGTT, we measured insulin sensitivity (insulin sensitivity index [ISI] Matsuda) and insulin secretion (homeostasis model assessment for the estimation of beta-cell secretion [HOMA-B], first- and second-phase insulin secretion). The product of the first-phase index and the ISI was calculated to obtain the insulin secretion-sensitivity index (ISSI).GDM was diagnosed in 17.9% and OAV in 18.7% of pregnant women; women with GDM and OAV were older and had higher BMI and serum triglyceride levels than those with NGT (all P0.05). Women with NGT had the highest ISI followed by those with OAV (-21.7%) and GDM (-32.1%). HOMA-B results were comparable with those for OAV and GDM but significantly (P0.01) lower than those for NGT; first- and second-phase insulin secretion appeared progressively reduced from that in women with NGT to that in women with OAV and GDM (P0.01). ISSI was higher in women with NGT than in women with either OAV (-34%) or GDM (-51.7%) (P0.001). Among OAV subgroups, the 1h-OAV subgroup showed the lowest ISSI (P0.05).OAV and GDM are clinically indistinguishable, and both groups are different from women with NGT. Women with GDM and OAV showed impaired insulin secretion and insulin sensitivity, although these defects are more pronounced in women with GDM. Compared with other OAV subgroups, 1h-OAV could be considered a more severe condition.

The aim of this prospective study was to evaluate the efficacy of the implementation of the International Consensus on the Diabetic Foot (ICDF) in the area of Pistoia (Tuscany, Italy), in terms of percentage of population screened, reduction of hospitalization, and reduction of lower extremity amputations. The study was carried out over a 5-year period (1999-2003) in a district general hospital covering a clearly defined and relatively static population. The implementation of ICDF was performed at district health care level, in collaboration with general practitioners, and at the hospital with the establishment of a multidisciplinary care team. The database for this study was extracted from the DRG Tuscany database, and the diabetes foot lesion data source was taken from the Data Elaboration Centre of the Health Care District of Pistoia, cross-checked with the clinical records of the Diabetes Unit. In the period of the study, there was an increase in both the total number of diabetic foot lesions observed and the number of patients with diabetes referred for evaluation to the Diabetes Unit of Pistoia. Following implementation, the total number of hospitalizations for diabetic foot lesions and the duration of clinical stay were reduced. The total incidence of amputations per 100,000 inhabitants decreased from 10.7 in 1999, to 10.1 in 2000, 2.7 in 2001, 6.3 in 2002 and 6.24 in 2003. In particular, while the incidence of major amputations decreased over time, the relative number of minor amputations increased in the first years, stabilizing at a higher rate in later years. Finally, while before 1999 most people from the Pistoia area were referred to various hospitals in Tuscany for diabetic foot problems, during the implementation period almost all were referred to the Diabetic Unit of Pistoia. This study shows the advantages of prospective data collection, demonstrating that the implementation of the International Consensus on the Diabetic Foot can improve foot care in diabetes.

Serum homocysteine (sHcy) has been found to be elevated in patients with type 2 diabetes mellitus, as well as in other clinical conditions associated with insulin resistance and/or vascular diseases. The aims of this study were to measure the relationship between sHcy with biohumoral markers of insulin resistance in pregnant women affected with gestational diabetes mellitus (GDM). We studied 2 groups of pregnant women categorized, after a 100-g, 3-hour oral glucose tolerance test (OGTT) as nondiabetic (n = 78) or affected with GDM (n = 15), by measuring sHcy, serum folate, albumin, vitamin B(12), uric acid, and lipids. In both groups, peripheral insulin sensitivity was measured by using the OGTT-derived index of Matsuda and DeFronzo (ISI(OGTT)). Serum homocysteine was significantly higher in the group with GDM compared with nondiabetic women (5.88 +/- 2.26 micromol/L v 4.45 +/- 1.52 micromol/L; P =.003); was inversely related to serum folate (r = -.48; P =.0001), and was significantly related to serum albumin (r =.27; P =.009), 2-hour plasma glucose (r =.25; P =.01), as well as to serum uric acid (r =.23; P =.03). No relationship was observed between sHcy and serum vitamin B(12), serum triglycerides, total, or high-density lipoprotein (HDL) cholesterol, mean blood pressure and ISI(OGTT). Vitamin B(12) was correlated with ISI(OGTT) (r =.36; P =.0005) and inversely with mean blood pressure (r = -.24; P =.02). GDM remained significantly associated with higher sHcy concentrations also after adjusting for age, serum folate, albumin, uric acid, ISI(OGTT), and vitamin B(12) (P =.006). In conclusion, we found that sHcy is significantly increased in women with GDM, independently of other confounding variables, is significantly related to 2-hour OGTT plasma glucose, and seems unrelated to insulin resistance in these subjects.

OBJECTIVE—To study the relationship between low birth weight and the presence of gestational diabetes mellitus (GDM) or peripheral insulin resistance during pregnancy. RESEARCH DESIGN AND METHODS—We studied the relationship between peripheral insulin sensitivity (calculated by Matsuda and DeFronzo’s oral glucose tolerance test (OGTT)-derived insulin sensitivity index [ISIOGTT]) or GDM prevalence and birth weight in 604 pregnant women, classified as normally glucose tolerant (n = 462) or affected with GDM (n = 142) after a 100-g 3-h oral glucose tolerance test. We then categorized these subjects into two groups: individuals with birth weight in the 10th percentile (n = 536). RESULTS—GDM prevalence was higher in the group in the lowest birth weight decile ( CONCLUSIONS—Low maternal birth weight was associated with a twofold higher risk for GDM, independent of major confounders. Such a risk was highest in women with low birth weight who delivered macrosomic babies, and in the group with low birth weight, the relationship between maternal glucose tolerance or insulin resistance and offspring’s neonatal weight was much more evident.

Background: The measurement of the peroxidase scavenging system represented by the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) in blood cells of diabetic patients has, in the past, given equivocal results. Likewise, the role of these intracellular enzymatic scavengers against the oxidative stress of diabetes-associated microangiopathic complications is unknown. Methods: Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of SOD, catalase and GSH-Px to the presence of diabetes, as well as to the presence of nephropathy and retinopathy in 35 insulin-dependent diabetic patients, as compared to 10 age-matched control subjects. Results: The enzymatic activities were not changed in diabetic patients in comparison with healthy controls. After stratifying patients according to presence of nephropathy (24-h urinary albumin excretion rate persistently ≥20 μg min−1) or retinopathy, the group of albuminuric patients was characterized by a significant decrease in SOD activity as compared to those in the normoalbuminuric range (4.36±1.06 vs. 6.81±2.26 mU 10−9 platelets; p=0.01). Catalase and GSH-Px did not change. No modification in platelet enzyme activities has been found in diabetic subjects with retinopathy. Conclusions: These results suggest that diabetic nephropathy, at least in its early stage, may be related to an altered redox state of platelets, as tested by the reduction in SOD activity, thus, indicating that the renal damage in these patients may be associated to a selective increase in platelet susceptibility to variation in the redox state.

Roberto Anichini,1 Sabrina Cosimi,2 Alberto Di Carlo,3 Paola Orsini,4 Alessandra De Bellis,1 Giuseppe Seghieri,1 Flavia Franconi,5 Fabio Baccetti6 1Diabetes Unit, Spedali Riuniti, Pistoia, Italy; 2Diabetes Unit, Hospital of Versilia, Camaiore (LU), Italy; 3Diabetes Unit, Hospital of Lucca, Italy; 4Diabetes Unit, Hospital of Livorno, Italy; 5Department of Biochemical Sciences, University of Sassari, Italy; 6Diabetes Unit, Hospital of Massa, Italy Purpose: To investigate whether gender affects therapeutic response by exenatide twice a day (BID) in type 2 diabetes by using a database concerning patients monitored by five outpatient clinics in Tuscany, Italy. Patients and methods: We considered a cohort of 315 (154 male/161 female) patients experiencing therapeutic failure while on oral therapy (metformin, or combination therapy metformin + sulphonylureas), who were given exenatide (10 µg/BID) and who fully completed 4 months, 8 months, and 12 months of follow-ups. Results: Among patients stratified by gender and well matched for age, body mass index, and hemoglobin A1c (HbA1c), it was found that the length of disease was longer in females than in males (12 ± 8 years versus 10 ± 7 years; P = 0.037), and the ratio of patients on metformin to those on combination therapy was higher in men (P = 0.018). Target glycemic response (1-year HbA1c ≤ 7%) was achieved in a significantly higher proportion of males than females (38% versus 27%;Χ2 = 4.66; P = 0.03). Target weight loss expressed as 1-year weight percent fall from baseline ≥ 75th percentile (8.5%) was significantly higher in females at 8 and 12 months (P < 0.05; for both). One-year glycemic target response was inversely related to baseline HbA1c levels and diabetes duration among males, while metformin therapy (compared to oral combination therapy) was a significant predictor of better glycemic targets among females. Homeostasis model assessment-B, measured in 117 patients, predicted hypoglycemic response only in women (P = 0.009). Target 1-year weight loss was predicted by longer diabetes duration among males and by lower baseline HbA1c among females. Finally, no significant difference between genders was noted as to gastrointestinal side effects after exenatide therapy. Conclusion: According to this “real world” experience, predictors of glycemic control and body weight loss after 12 months of exenatide BID therapy are different between genders in type 2 diabetes. Keywords: GLP-1 agonist therapy, exenatide BID, type 2 diabetes, real world setting

I. Introduction IN 1953 lohn Morris, an obstetrician at Yale University, reported a series of 82 individuals (80 cases collated from the literature and two cases of his own) who had a female phenotype despite the presence of bilateral testes (1). Since his initial description, studies of the endocrinology, pathophysiology, biochemistry, and molecular biology of the androgen insensitivity syndrome (AIS) have provided insights into the role of androgens in male sex differentiation, the mechanisms of androgen action, and aspects of the structure/function relationships of the androgen receptor. AIS is an archetypal example of a hormone resistance disorder. Androgens are secreted by the testes of these 46,XY individuals in normal or increased amounts; however, due to defective androgen receptor (AR1) function, there is loss of target organ response to the hormone, and the effects of androgens are reduced or absent. Clinical disorders of the AR are reported far more commonly than resistance disorders of other m...

Denaturing gradient gel electrophoresis (DGGE) separates DNA molecules based on primary sequence. Under the appropriate conditions, all base pair (bp) substitutions, frame-shifts, and deletions less than about 10 bp can be resolved from the wild type sequence using DGGE. Polymerase chain reaction (PCR) permits facile amplification of a given region of the genome. We have combined PCR and DGGE to: (i) Localize mutations in the X-linked human androgen receptor gene. PCR/DGGE was used to screen the individual exons in the 2757-bp coding region of the gene in afflicted individuals as well as in potential carriers. Inheritance of a mutant allele has been demonstrated in several cases; (ii) Analyze thousands of thioguanine-resistant mutants simultaneously. The in vitro mutational spectra of MNNG, ICR-191, and cisplatin at the human HPRT locus have been examined by this method. The compounds all have mutational hotspots in a GGGGGG sequence in exon 3; however, the particular mutations induced by the agents were different; (iii) Examine the fidelity of several DNA polymerases used in PCR. The fidelity of Thermus aquaticus DNA polymerase (Taq) is 1-2 x 10(-4) misincorporations/bp/replication. Problems with Taq polymerase arise in the analysis of complex mutant populations by DGGE because the Taq-induced errors reduce the sensitivity of the system. To circumvent this, it had been necessary to use Sequenase, a modified T7 DNA polymerase with a higher fidelity. However, Sequenase is not thermostable and must be added every PCR cycle. A thermostable DNA polymerase from Thermococcus litoralis (Vent) is now available, and we have examined the fidelity of Vent, Taq, and Sequenase polymerase in PCR using DGGE. The fidelity of Vent, Taq, and Sequenase polymerase was 2.4 x 10(-5), 8.9 x 10(-5), and 4.4 x 10(-5) errors/bp, respectively. Vent polymerase had the highest fidelity of the three enzymes tested.

We characterized the epidermal growth factor (EGF) receptor in the membrane fraction of prostatic tissue from men with benign prostatic hyperplasia (BPH). The maximum specific binding of [125I]EGF to the BPH membrane fraction was achieved after 30-min incubation at 35 C. Analysis of the binding data revealed two classes of binding sites, one of high affinity [Kd, 2.5 +/- 0.5 (+/- SE) x 10(-11) mol/L] and one of lower affinity (2.2 +/- 0.3 x 10(-9) mol/L). [125I]EGF binding was inhibited by excess EGF, but not by insulin, proinsulin, fibroblast growth factor, or insulin-like growth factors I and II. In prostatic tissue of men with BPH treated for 3 months with the GnRH agonist analog Goserelin (Zoladex, depot formulation), the binding capacities of both sites were significantly higher than those of BPH tissue from untreated men (P less than 0.001). These results demonstrate that prostatic tissue from men with BPH contains two classes of specific binding sites for EGF, and their levels are modulated by chronic GnRH agonists treatment.

Hyperuricemia has previously been described as a strong predictor of well-defined cerebrovascular complications (stroke) in a Finnish cohort of patients with type 2 diabetes (1). To evaluate whether serum uric concentration would be selectively associated with presence of stroke as compared with transient ischemic attack (TIA) in a group of hospitalized diabetic patients, we studied 835 patients (220 affected with type 2 diabetes and 615 nondiabetic subjects), who were consecutively admitted to and subsequently discharged from our hospital for TIA ( n = 386) or stroke ( n = 449) during the period 1 January 1998 to 31 December 1999. Stroke was classified by means of computerized tomography as ischemic (thromboembolic) in 363 cases (81%) and hemorrhagic in …